Denys–Drash syndrome

Overview

Denys–Drash syndrome (DDS) is a rare but serious genetic disorder that primarily affects the kidneys and reproductive system. It is most commonly diagnosed in early childhood and is characterized by a triad of features: early-onset nephrotic syndrome, progressive kidney failure, and disorders of sexual development (particularly in individuals with a 46,XY karyotype). Additionally, children with DDS have an increased risk of developing Wilms tumor, a type of kidney cancer. The condition is named after Drs. Denys and Drash, who first described the syndrome in the 1970s.

Causes

Denys–Drash syndrome is caused by mutations in the WT1 gene located on chromosome 11p13. This gene plays a crucial role in the development of the kidneys and gonads. The condition follows an autosomal dominant inheritance pattern, but most cases are due to de novo (new) mutations that occur spontaneously. The WT1 mutation disrupts the function of the Wilms tumor suppressor protein, leading to abnormal kidney development, impaired filtration, and an increased risk of tumor formation.

Symptoms

Symptoms of Denys–Drash syndrome usually appear in infancy or early childhood and may include:

• Nephrotic syndrome: Characterized by proteinuria (excessive protein in urine), hypoalbuminemia (low blood albumin), edema (swelling), and high cholesterol levels.

• Progressive kidney failure: Gradual decline in kidney function, often leading to end-stage renal disease (ESRD) within the first few years of life.

• Disorders of sex development (DSD): In 46,XY individuals, there may be ambiguous genitalia, undescended testes, or pseudohermaphroditism. 46,XX individuals usually have normal female genitalia.

• Wilms tumor: A high risk of developing this pediatric kidney cancer, often requiring regular screening and surveillance.

Diagnosis

Diagnosis of Denys–Drash syndrome is based on a combination of clinical findings, laboratory tests, imaging studies, and genetic analysis. Diagnostic steps include:

• Urinalysis: Detects significant proteinuria, a hallmark of nephrotic syndrome.

• Blood tests: Reveal low serum albumin, elevated cholesterol, and signs of kidney dysfunction (e.g., high creatinine levels).

• Renal biopsy: Often shows diffuse mesangial sclerosis, a specific pattern of kidney damage associated with DDS.

• Ultrasound or MRI: Used to detect Wilms tumor or other structural abnormalities in the kidneys or reproductive organs.

• Genetic testing: Confirms mutations in the WT1 gene, solidifying the diagnosis.

• Karyotyping: Performed in patients with genital anomalies to determine chromosomal sex (e.g., 46,XY or 46,XX).

Treatment

Treatment of Denys–Drash syndrome is multidisciplinary, involving nephrology, oncology, endocrinology, and genetics. Management focuses on addressing kidney failure, preventing or treating tumors, and managing hormonal or genital abnormalities. Treatment options include:

• Kidney management: Supportive care for nephrotic syndrome, often progressing to dialysis and eventual kidney transplantation.

• Prophylactic nephrectomy: Surgical removal of the kidneys may be recommended to prevent Wilms tumor in high-risk patients.

• Wilms tumor treatment: If the tumor develops, it is treated with surgery, chemotherapy, and/or radiation.

• Hormonal therapy: In 46,XY individuals with ambiguous genitalia, hormone replacement therapy may be considered based on gender identity and medical needs.

• Genital surgery: May be performed to correct ambiguous genitalia or undescended testes.

• Psychosocial support: Essential for the child and family, particularly regarding decisions related to sex development and gender identity.

Prognosis

The prognosis of Denys–Drash syndrome depends on early diagnosis, the severity of kidney involvement, and timely treatment of Wilms tumor if present. Without treatment, most children progress to end-stage renal disease by age 3–4. However, with early kidney transplantation and cancer surveillance, many children can achieve improved long-term outcomes. Nevertheless, the condition is serious and requires lifelong medical monitoring and support across multiple specialties.